Tachyarrhythmia generally refers to a heart rate that is faster than 90 beats per minute. In case of severe coronary stenosis or other severe cardiac diseases heart rates faster than 80 bpm may be considered too high (relative tachycardia).
Tachyarrhythmias may be responsible for worsening heart failure, stroke, myocardial infarction or sudden death. They may be primary or occur secondary to underlying cardiac, pulmonary or endocrine disease.
Tachyarrhythmias can be either physiologic such as sinus tachycardia occurring during exercise or pathologic as during atrial or ventricular tachycardia which can occur when irritable cells in the heart muscle or heart's electrical conduction system start to fire faster than the heart's normal rhythm. Tachyarrhythmias can start in either the upper heart chambers (atria) or lower heart chambers (ventricles). An atrial (=supraventricular) tachyarrhythmia starts in the atria and is generally classified as being atrial tachycardia (AT), atrial flutter, or tachycardic atrial fibrillation (AF). A ventricular tachyarrhythmia starts in the ventricles and is generally classified as being either a ventricular tachycardia (VT) or ventricular fibrillation (VF).
Supraventricular tachyarrhythmia is a major post-operative complication, and develops with the high frequency of 11-40% after coronary artery bypass surgery; therefore, this condition plays an important role in increased postoperative complications and duration of hospitalization (Murakami M., et al., Drug Metab. Pharmacokinet., 2005, 20(5), 337-344).
Tachycardia can be life-threatening because it can lead to ventricular fibrillation, in which the heart beats rapidly in a chaotic, purposeless fashion such that the heart cannot pump blood effectively to the body. If untreated, fibrillation can be fatal.
Long-standing tachycardia is well recognized for its potential to induce a dilated cardiomyopathy. While the exact incidence of tachycardia-mediated cardiomyopathy remains unclear, an association between tachycardia and cardiomyopathy has been recognized. Virtually every form of supraventricular tachyarrhythmia, including ectopic atrial tachycardia, nonparoxysmal junctional tachycardia, and atrial fibrillation (AF), has been associated with reversible left ventricular dysfunction or “cardiomyopathy.” The development of a cardiomyopathy has also been documented with ventricular tachyarrhythmias and frequent ventricular premature beats.
Tachyarrhythmias are often treated with β-blockers which have been reported to be effective regulators of heart rate and sinus rhythm. Beta-blockers were considered useful specifically for the short and long term treatment of such diseases. These β adrenergic receptor-antagonists competitively block beta receptors, thereby inhibiting cAMP formation and preventing the events that routinely follow. β1 receptor blockade causes a decrease in cardiac inotropy, chronotropy, and automaticity, culminating in a reduction of cardiac output.
There are three subgroups of beta receptors. Although these receptors may be found in more than one location in the human body, β1 receptors are primarily found on cardiac myocytes, β2 receptors are located chiefly in vascular and bronchial smooth muscle, β3 receptors are concentrated in adipocytes, although being found in cardiac myocytes, too. During stressful conditions, endogenous catecholamine release stimulates β1 receptors to promote an increase in the heart rate and contractility, whereas β2 receptor stimulation induces branchiolar and arteriolar dilation. Agonists also promote insulin release glycogenolysis, and gluconeogenesis (Anderson A. C., 2008, Clin. Ped. Emergency Med., 4-16).
Blockade of β1 receptors also leads to suppression of renin secretion in the kidney, thereby decreasing production of angiotensin II (a potent vasoconstrictor) and aldosterone (which promotes sodium retention). The combination of renal effects and reduced cardiac output promotes a decrease in the blood pressure. Blocking vascular smooth muscle β2 receptors provides a rise in vascular tone that is clinically insignificant in most instances.
Hypertension (HTN) or high blood pressure, sometimes called arterial hypertension, is a medical condition in which the blood pressure in the arteries is elevated. Blood pressure is summarised by two measurements, systolic and diastolic, which depend on whether the heart muscle is contracting (systole) or relaxed between beats (diastole). This equals the maximum and minimum pressure, respectively. Normal blood pressure at rest is within the range of 100-140 mmHg systolic (top reading) and 60-90 mmHg diastolic (bottom reading). High blood pressure is said to be present if it is often at or above 140/90 mmHg.
Hypertension is classified as either primary (essential) hypertension or secondary hypertension; about 90-95% of cases are categorized as “primary hypertension” which means high blood pressure with no obvious underlying medical cause. The remaining 5-10% of cases (secondary hypertension) are caused by other conditions that affect the kidneys, arteries, heart or endocrine system.
Hypertension puts strain on the heart, leading to hypertensive heart disease and coronary artery disease if not treated. Hypertension is also a major risk factor for stroke, aneurysms of the arteries (e.g. aortic aneurysm), peripheral arterial disease and is a cause of chronic kidney disease. A moderately high arterial blood pressure is associated with a shortened life expectancy while mild elevation is not. Dietary and lifestyle changes can improve blood pressure control and decrease the risk of health complications, although drug treatment is still often necessary in people for whom lifestyle changes are not enough or not effective.
Esmolol hydrochloride, the first ultra short-acting adrenergic β1 adrenoreceptor blocking agent, has been widely used to aid control of tachycardia and hypertension. Esmolol is an ultra short-acting intravenous cardioselective beta-antagonist. It has an extremely short elimination half-life (mean: 9 minutes; range: 4 to 16 minutes) and a total body clearance [285 ml/min/kg (17.1 L/h/kg)] approaching 3 times cardiac output and 14 times hepatic blood flow. The alpha-distribution half-life is approximately 2 minutes. When esmolol is administered as a bolus followed by a continuous infusion, onset of activity occurs within 2 minutes, with 90% of steady-state beta-blockade occurring within 5 minutes. Full recovery from beta-blockade is observed 18 to 30 minutes after terminating the infusion. Esmolol blood concentrations are undetectable 20 to 30 minutes post infusion. The elimination of esmolol is independent of renal or hepatic function as it is metabolised by red blood cell cytosol esterases to an acid metabolite and methanol. The acid metabolite, which is renally eliminated, has 1500-fold less activity than esmolol. Clinically, esmolol was used in the past for the following: (i) situations where a brief duration of adrenergic blockade is required, such as tracheal intubation and stressful surgical stimuli; and (ii) critically ill or unstable patients in whom the dosage of esmolol is easily titrated to response and adverse effects are rapidly managed by termination of the infusion. In adults, bolus doses of 100 to 200 mg are effective in attenuating the adrenergic responses associated with tracheal intubation and surgical stimuli. For the control of supraventricular arrhythmias, acute postoperative hypertension and acute ischaemic heart disease, doses of <300 μg/kg/min, administered by continuous intravenous infusion, are used. The principal adverse effect of esmolol is hypotension (incidence of 0 to 50). The incidence of hypotension appears to increase with doses exceeding 150 μg/kg/min and in patients with low baseline blood pressure. Hypotension infrequently requires any intervention other than decreasing the dose or discontinuing the infusion. Symptoms are generally resolved within 30 minutes after discontinuing the drug. In surgical and critical care settings where clinical conditions are rapidly changing, the pharmacokinetic profile of esmolol allows the drug to provide rapid pharmacological control and minimises the potential for serious adverse effects.
Miwa Y. et al. (2010, Circulation Journal, 74, 856-863) describe the effect of landiolol in the treatment of electrical refractory storm.
Takahashi S. et al. (2000, Can. J. Anesth., 47, 265-272) describe studies on the effect of landiolol on hemodynamic response to acute theophylline intoxication inducing tachyarrhythmia in animals.
Morisaki A. et al. (2012, Gen. Thorac. Cardiovasc. Surg., 60, 386-390) describes continuous very-low-dose of 2 μg/kg/min-5 μg/kg/min of landiolol for about 10 days in treating postoperative atrial tachycardia in patients with poor left ventricular function.
Wariishi S. et al. (2009, Interactive Cardiovasc. Thoracic Surgery, 9, 811-813) describes the low dose administration of landiolol hydrochloride in patients with postoperative supraventricular arrhythmia.
Studies on different doses of landiolol hydrochloride infused for eleven minutes during anesthesia in patients of different age and sex are disclosed by Mizuno J. et al. (2007, Eur. J. Clin. Pharmacol., 63, 243-252).
Kubo K. et al. (2005, J. Anesth., 19, 174-176) describe the use of landiolol at a dose of 40 ug/kg/min during cesarean section in a patient with Romano-Ward syndrome. Administration was stopped 10 minutes before end of surgery.
Nagai R. et al. (2013, Circulation J., 77, 908-916) disclose the use of landiolol to control tachycardia in patients with left ventricular dysfunction. The dosage is adjusted to the range of 1-10 μg/kg/min.
It was shown that long-term administration of beta-blockers can be associated with an increase in myocardial β-adrenergic receptor density (Hellbrunn S. et al., Circulation, 1989, 79, 483-490, Nanoff C. et al., 1990, Basic Res. Cardiol., 85, 88-95). The β-adrenergic receptor increase may not only lead to the restoration of β-adrenergic sensitivity in cases of heart failure treatment but, in cases of tachycardia, it may also lead to a beta-blocker tolerance which thus needs increased dosages and shorter administration intervals.
It has been reported that sudden discontinuation of the administration of similar compounds (propranolol hydrochloride) from patients who suffered from angina or other coronary heart diseases worsened the condition or led to cardiac infarction (Harrison D C and Alderman E L, 1976, Chest, 69(1), 1-2; Hausen T., 1981, MMW Münch Med Wochenschr., 123(42), 1583-4). In data sheets for Ono Act (landiolol hydrochloride, Ono Pharmaceuticals. Revised edition November 2012) and esmolol hydrochloride (Brevibloc, Aug. 10, 2009) it is noted that careful observation is required when discontinuing the administration of landiolol or that an overshoot after termination of esmolol administration cannot be ruled out.
Additionally, sensitization of receptor mediated response may lead to withdrawal syndromes after termination of beta-blocker administration (Peters J. R. et al., 1985, 107, 43-52).
Furthermore, long term treatment with intravenously administered beta-blockers can lead to negative side effects such as infusion site reactions including inflammation and induration, like edema, erythema, skin discoloration, burning at the infusion site, thrombophlebitis, and local skin necrosis from extravasation phlebitis, which side effects are commonly minimized by administering the diluted formulation.
There is still an unmet demand for providing a long-term treatment of tachyarrhythmia or tachycardia that avoids negative side effects but are effective in the treatment without the need of increasing the dosage due to tolerance effects thereby promoting vascular irritation and overshoot reactions.